TY - JOUR
T1 - Targeting superoxide dismutase 1 to overcome cisplatin resistance in human ovarian cancer
AU - Brown, Dawn P.G.
AU - Chin-Sinex, Helen
AU - Nie, Bei
AU - Mendonca, Marc S.
AU - Wang, Mu
PY - 2009/3
Y1 - 2009/3
N2 - Purpose: Clinical drug resistance to platinum-based chemotherapy is considered a major impediment in the treatment of human ovarian cancer. Multiple pathways associated with drug resistance have been suggested by many previous studies. Over expression of several key proteins involved in DNA repair, drug transport, redox regulation, and apoptosis has been recently reported by our group using a global quantitative proteomic profiling approach. Superoxide dismutase 1 (SOD1) is one of these proteins consistently over-expressed in cisplatin-resistant ovarian cancer cells as compared to their sensitive counterparts, but its precise role in drug resistance is yet to be defined. Method: In the current study, we examined the role of SOD1 in drug resistance by inhibiting its redox activity in cisplatin-resistant ovarian cancer cells using a small-molecule inhibitor, triethylenetetramine (TETA). The effect of TETA was determined by the cell proliferation assay, clonogenic cell survival assay, and SOD1 activity assay. Results: The inhibition of the SOD1 activity enhanced the cisplatin sensitivity in the resistant cells supporting the hypothesis that SOD1 is a key determinant of cisplatin resistance and is an exploitable target to overcome cisplatin drug resistance. Conclusion: SOD1 plays an important role in cisplatin resistance and modulation of its activity may overcome this resistance and ultimately lead to improved clinical outcomes.
AB - Purpose: Clinical drug resistance to platinum-based chemotherapy is considered a major impediment in the treatment of human ovarian cancer. Multiple pathways associated with drug resistance have been suggested by many previous studies. Over expression of several key proteins involved in DNA repair, drug transport, redox regulation, and apoptosis has been recently reported by our group using a global quantitative proteomic profiling approach. Superoxide dismutase 1 (SOD1) is one of these proteins consistently over-expressed in cisplatin-resistant ovarian cancer cells as compared to their sensitive counterparts, but its precise role in drug resistance is yet to be defined. Method: In the current study, we examined the role of SOD1 in drug resistance by inhibiting its redox activity in cisplatin-resistant ovarian cancer cells using a small-molecule inhibitor, triethylenetetramine (TETA). The effect of TETA was determined by the cell proliferation assay, clonogenic cell survival assay, and SOD1 activity assay. Results: The inhibition of the SOD1 activity enhanced the cisplatin sensitivity in the resistant cells supporting the hypothesis that SOD1 is a key determinant of cisplatin resistance and is an exploitable target to overcome cisplatin drug resistance. Conclusion: SOD1 plays an important role in cisplatin resistance and modulation of its activity may overcome this resistance and ultimately lead to improved clinical outcomes.
KW - Cisplatin resistance
KW - Mass spectrometry
KW - Ovarian cancer
KW - Reactive oxygen species
KW - Superoxide dismutase 1
UR - http://www.scopus.com/inward/record.url?scp=58849115018&partnerID=8YFLogxK
U2 - 10.1007/s00280-008-0791-x
DO - 10.1007/s00280-008-0791-x
M3 - Article
C2 - 18622615
AN - SCOPUS:58849115018
SN - 0344-5704
VL - 63
SP - 723
EP - 730
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 4
ER -
